With the sequencing of the human genome, it is becoming more widely accepted that protein-protein interactions are an important aspect of how biological complexity is generated. Chemical tools to detect and study protein-protein association will provide a deeper understanding of the nature, regulation and function of these interactions, which is central to human health. This proposal is aimed at developing Lanthanide Binding Tags (LBTs), comprised of 15-21 natural encoded amino acids which bind lanthanide ions, as fluorescent probes to detect protein-protein interactions. The research project begins with optimization of nano-molar binding LBTs to obtain even more selective binding. This will be achieved using a combination of rational design and combinatorial screening. The optimized LBT will then be split into two fragments that are fused to two respective proteins. Association of the proteins should lead to reconstitution of the LBT resulting in a fluorescent signal. This signal can then be detected as a measurement of the proteins interactions. This new chemical tool will be developed to study known and unknown protein-protein interactions.